Beta-lactam compounds process for reproducing the same and serum cholesterol-lowering agents containing the same

ABSTRACT

Novel β-lactam compounds represented by the following general formula (I) or pharmaceutically acceptable salts thereof which are useful as serum cholesterol-lowering agents: (I) wherein A 1 , A 3  and A 4  represent each hydrogen, halogen, C 1-5  alkyl, C 1-5  alkoxy, —COOR 1 , a group represented by the following general formula (b): (b) wherein R 1  represents hydrogen or C 1-5  alkyl, or a group represented by the following general formula (a): (a) wherein R 2  represents —CH 2 OH, —CH 2 OC(O)—R 1  or —CO 2 —R 1 ; R 3  represents —OH or —OC(O)—R 1 ; R 4  represents —(CH 2 ) k R 5 (CH 2 ) l — wherein k and l are each 0 or an integer of 1 or above provided k+l is an integer of not more than 10; and R 5  represents a single bond, —CH═CH—, —OCH 2 —, carbonyl or —CH(OH)—; provided that at least one of A 1 , A 3  and A 4  is a group represented by the above formula (a); A 2  represents C 1-5  alkyl, C 1-5  alkoxy, C 1-5  alkenyl, C 1-5  hydroxyalkyl or C 1-5  carbonylalkyl; and n, p, q and r are each an integer of 0, 1 or 2.

FIELD OF THE INVENTION

[0001] This invention related to novel β-lactam compounds, amanufacturing method of these compounds and a serum hypocholesterolemicagent contained these compounds.

BACKGROUND OF THE INVENTION

[0002] Hypercholesterolemia is a risk factor for atherosclerotic heartdisease. Atherosclerotic heart disease represents the major cause fordeath and cardiovascular morbidity in the world (Lipid Research ClinicsProgram. J.Am.Med.Assoc., 1984, 251, 351 or 365). Recently, HMG-CoAreductase inhibitors have been used as the hypocholesterolemic agents inclinical. HMG-CoA reductase inhibitors are shown to have a potent serumhypocholesterolemic activity, however, they are also reported to haveunfavorable side effects (Mevacor in Physician's Desk Reference, 49thED, Medical Economics Date Production Company, 1995, 1584). Therefore,the potent and safety serum hypocholesterolemic agents are desired.

[0003] It has been reported that naturally occuring glycosides haveserum hypocholesterolemic activity (M. A. Farboodniay Jahromi et al.,J.Nat.Prod., 1993, 56, 989., K. R. Price, The Chemistry and BiologicalSignificance of Saponins in Fords and Feeding Stuffs. CRC CriticalReviews in Food Science and Nutrition, CRC Press, 1987, 26, 27). It isconsidered that these glycosides reduce serum cholesterol levels due tothe inhibition of cholesterol absorption in small intestine (P. A.McCarthy et al., J.Med.Chem., 1996, 39, 1935). Additionally, someβ-lactam compounds are reported its hypocholesterolemic activity (S. B.Rosenblum et al., J.Med.Chem., 1998, 41, 973, B. Ram et al., IndianJ.Chem., 1990, 29B, 1134. USP 489, 3597).

[0004] The β-Lactam compounds have a weak inhibitiory activity oncholesterol absorption themselves, and further the glucuronide of theβ-lactam compounds are more potent than the parent β-lactams. In theabsorption process, the β-lactam compounds are rapid glucuronidated insmall intestine after oral administration, and the resulting glucuronidederivatives are secreted through bile-duct to small intestine. Theseβ-lactam-O-glucuronic acid conjugated derivatives are located to mucosallayer in small intestine, a site of action, and inhibit cholesterolabsorption (M. van Heek et al., Brit.J.Pharmacol.,2000,129,1748,J.Pharmacol.Exp.Ther.,1997,283,157). Because of the above mentionedβ-lactam compounds show serum hypocholesterolemic activity in smallintestine by β-lactam-O-glucuronate conjugated derivatives, thehypocholesterolemic activities of these compounds incorporating glucoseor glucuronic acid derivatives were synthesized (W. D. Vaccaro et al.,Bioorg.Med.Chem.Lett., 1998, 8, 313). However, it is considered that theO-glycoside bonds in these compounds are readily hydrolyzed withglycosidase existed in small intestine after oral administration, and itis supposed the hypocholesterolemic activities of these compounds insmall intestine will be reduced. Thinking about the active site of theseβ-lactams is mucosal layer in small intestine, the better cholesterolabsorption inhibitors are required to act just only in small intestinewith high efficacy and long duration. It is expected that idealcholesterol absorption inhibitors are not to be absorbed in smallintestine and eliminated without absorption in small intestine so thatside effects will be reduced after the absorption in small intestine.

[0005] The principal object of the present invention is the provision ofnovel hypocholesterolemic agents having β-lactam moiety and C-glycosidein the molecules, which is stable to metabolism by glycosidase andhydrolysis with acids or bases. Namely, the object of the presentinvention is the provision of hybrid molecules with β-lactam andC-glycoside as hypocholesterolemic agents.

DETAILED DESCRIPTION OF THE INVENTION

[0006] We thought that the β-lactam and C-glycosides hybride compoundsare metabolically stable against glycosidase and hydrolysis with acidsor bases (R. J. Linhald et al., Tetrahedron,54,9913-9959,1998). Firstly,the β-lactam-C-glycoside compounds are expected to be stable againstglycosidase existed in small intestine and these hybrids were possibleto locate at mucosal layer in small intestine in long time. Secondly, wethought that these compounds were little absorbed at mucosal layer insmall intestine so that the side effects will be reduced. In the effortfor the discovery of novel β-lactam compounds having serumhypocholesterolemic activity, we found that the compounds of the generalformula (I) are the excellent hypocholesterolemic agents

[0007] Namely, the compounds of the present invention have the followinggeneral formula (I):

[0008] [wherein: A₁, A₃ and A₄ are hydrogen atom, halogen atom, alkylgroup having one to five carbon atoms, alkoxy group having one to fivecarbon atoms, —COOR₁, a following formula (b):

[0009] (wherein: R₁ is a hydrogen atom or an alkyl group having one tofive carbon atoms) or a following formula (a):

[0010] (wherein: R₂ is —CH₂OH group, —CH₂OC(O)—R1 group or —CO₂—R₁group; R₃ is —OH group or —OC(O)—R₁ group; R₄ is —(CH₂)_(k)R₅(CH₂)_(l)—(k and l are 0 or 1 more integer; k+l is 10 or fewer integer); R₅ meansbond (single bond (—), —CH═CH—, —OCH₂—, carbonyl group or —CH(OH)—.).

[0011] One of A₁, A₃ and A₄ in formula (I) is must be the group in abovementioned formula (a). A₂ is alkyl chain having one to five carbonatoms, alkoxy chain having one to five carbon atoms, alkenyl chainhaving one to five carbon atoms, hydroxyalkyl chain having one to fivecarbon atoms or carbonylalkyl chain having one to five carbon atoms. n,p, q or r are 0, 1 or 2.] or their pharmaceutical acceptable salts.

[0012] Furthermore, this invention related to a mamufacturing method ofthe compounds of general formula (I) and pharmaceutically acceptablesalts thereof. This invention also related to a serumhypocholesterolemic agent contained the compounds of general formula (I)and their pharmaceutically acceptable salts. Additionally, thisinvention related to a serum hypocholesterolemic agent by combinationtherapy of the compounds of general formula (I) and β-lactamaseinhibitors.

[0013] Pharmaceutically acceptable salts of this invention are mentionedas follow. As mineral basic salt, sodium or potassium salts of generalformula (I) are mentioned. As organic acid salts, succinic acid, maleicacid, toluenesulfonic acid or tartaric acid are mentioned. The compoundsof general formula (I) can be orally administered alone or incombination with pharmaceutically acceptable carriers or diluents. Theymay be administed orally as powders, granules, tablets, capsules bystandard pharmaceutical techniques and also parenterally as intrarectaladministrations, suppositories and injections.

[0014] The dosage is ranging from 0.01-1000 mg per day and administeredin a single dose or several doses. However, variations will necessarilyoccur depending upon the conditions, age and body weight of therecipient. Additionally, serum hypocholesterolemic activity is enhancedin the combination with the compounds of the general formula (I) andβ-lactamase inhibitors.

[0015] The β-lactumase inhibitors such as clavulanic acid are a drugwhich inhibit to degradation of β-lactum ring by bacteria.

[0016] The compounds are exemplified as follows, although they did notbe limited.

[0017] (1)(4S*,3R*)-4-{4-[(2S,5S,3R,4R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]phenyl}-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)propyl]azetidine-2-one

[0018] (2)(4S*,3R*)-4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl)phenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)propyl]azetidine-2-one

[0019] (3)(3S,2R,4R,5R,6R)-2-[(4-{(4S*,3R*)-1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)propyl]-2-oxoazetidine-4-yl}phenyl)methyl]-4,5-diacetyloxy-6-(acetoxymethyl)perhydro-2H-pyran-3-ylacetate

[0020] (4)(4S*,3R*)-4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-1-(4-chlorophenyl)-3-[3-(4-fluorophenyl)propyl]azetidine-2-one

[0021] (5)(4S*,3R*)-4-(4-{[(5S,2R,3R,4R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-1-(4-methoxyphenyl)-3-[3-(4-fluorophenyl)propyl]azetidine-2-one

[0022] (6)(3S,2R,4R,5R,6R)-2-[(4-{(4S*,3R*)-1-(4-Methoxyphenyl)-3-[3-(4-fluorophenyl)propyl]-2-oxoazetidine-4-yl}phenyl)methyl]-4,5-diacetyloxy-6-(acetoxymethyl)perhydro-2H-pyran-3-ylacetate

[0023] (7)(4S*,3R*)-4-(4-{[(5S,2R,3R,4R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-1-(4-methylphenyl)-3-[3-(4-fluorophenyl)propyl]azetidine-2-one

[0024] (8)(3S,2R,4R,5R,6R)-2-[(4-{(4S*,3R*)-1-(4-Methylphenyl)-3-[3-(4-fluorophenyl)propyl]-2-oxoazetidine-4-yl}phenyl)methyl]-4,5-diacetyloxy-6-(acetoxymethyl)perhydro-2H-pyran-3-ylacetate

[0025] (9)(4S*,3R*)-4-(4-{[(5S,2R,3R,4R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-1-phenyl-3-[3-(4-fluorophenyl)propyl]azetidine-2-one

[0026] (10)(3S,2R,4R,5R,6R)-2-[(4-((4S*,3R*)-1-phenyl-3-[3-(4-fluorophenyl)propyl]-2-oxoazetidine-4-yl}phenyl)methyl]4,5-diacetyloxy-6-(acetoxymethyl)perhydro-2H-pyran-3-ylacetate

[0027] (11)(4S*,3R*)-4-(4-{[(5S,2R,3R,4R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-1-(4-fluorophenyl)-3-[3-(phenyl)propyl]azetidine-2-one

[0028] (12)(4S*,3R*)-4-(4-{[(5S,2R,3R,4R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-1-(4-fluorophenyl)-3-[2-(4-fluorophenoxy)ethyl]azetidine-2-one

[0029] (13)(3S,2R,4R,5R,6R)-2-[(4-{(4S*,3R*)-1-(4-Fluorophenyl)-3-[2-(4-fluorophenoxy)ethyl]-2-oxoazetidine-4-yl}phenyl)methyl]-4,5-diacetyloxy-6-(acetoxymethyl)perhydro-2H-pyran-3-ylacetate

[0030] (14)(4S*,3R*)-4-(4-{[(4S,5S,2R,3R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methoxy}phenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)propyl]azetidine-2-one

[0031] (15)(4S*,3R*)-4-(4-{[(4S,5S,2R,3R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methoxy}phenyl)-1-(4-fluorophenyl)-3-[2-(4-fluorophenoxy)ethyl]azetidine-2-one

[0032] (16)(4S*,3R*)-4-(4-{[(4S,5S,2R,3R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methoxy}phenyl)-1-phenylmethyl-3-[3-(4-fluorophenyl)propyl]azetidine-2-one

[0033] (17)(2S,3S,4R,5R,6R)-6-[4-{(4S*,3R*)-1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)propyl]-2-oxoazetidine-4-yl}phenyl)methyl]-3,4,5-trihydroxyperhydro-2H-pyran-2-carboxylicacid

[0034] (18)2-{4-[(4S*,3R*)-4-{[(5S,2R,3R,4R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl-3-[3-(4-fluorophenyl)propyl]-2-oxoazetidinyl]phenoxy}-2-methylpropionicacid ethyl ester

[0035] (19)2-{4-[(4S*,3R*)-4-{[(5S,2R,3R,4R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl-3-[3-(4-fluorophenyl)propyl]-2-oxoazetidinyl]phenoxy}-2-methylpropionicacid

[0036] (20)2-{4-[(4S*,3R*)-4-{[(5S,2R,3R,4R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl-3-[3-(4-methylphenyl)propyl]-2-oxoazetidinyl]phenoxy}-2-methylpropionic acid ethyl ester

[0037] (21)2-{4-[(4S*,3R*)-4-{[(5S,2R,3R,4R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl-3-[3-(4-methylphenyl)propyl]-2-oxoazetidinyl]phenoxy}-2-methylpropionicacid

[0038] (22)(4S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-1-(4-fluorophenyl)azetidine-2-one

[0039] (23)(4S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-1-phenylazetidine-2-one

[0040] (24)(4S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-1-(4-methylphenyl)azetidine-2-one

[0041] (25)(4S,3R)-4-(4-{[(5S,2R,3R,4R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl)methyl}phenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)propyl]azetidine-2-one

[0042] (26)(4S,3R)-4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidine-2-one

[0043] (27)(4S,3R)-4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-1-phenyl-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidine-2-one

[0044] (28)(4S,3R)-4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-1-(4-methylphenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidine-2-one

[0045] (29)4-[(4S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-2-oxoazetidinyl]benzoicacid

[0046] (30)4-[(4S,3R)-4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]-2-oxoazetidinyl]benzoicacid

[0047] (31)4-[(4S,3R)-4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-3-[3-(4-fluorophenyl)propyl]-2-oxoazetidinyl]benzoicacid

[0048] (32)3-[(2E)-3-(4-Fluorophenyl)-2-propenyl](4S,3R)-4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-1-(4-fluorophenyl)azetidine-2-one

[0049] (33)(4S,3R)-4-{4-{[(2S,5S,3R,4R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]phenyl}-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)propyl]azetidine-2-one

[0050] (34)(4S,3R)-4-{4-{[(2S,5S,3R,4R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]phenyl}-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidine-2-one

[0051] (35)(4S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-{4-{[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]phenyl}-1-(4-fluorophenyl)azetidine-2-one

[0052] (36)(4S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-{4-{[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]phenyl}-1-(4-methylphenyl)azetidine-2-one

[0053] (37)(4S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]-1-phenylazetidine-2-one

[0054] (38)(4S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-1-(4-{[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-1-(4-fluorophenyl)azetidine-2-one

[0055] (39)(4S,3R)-3-[(3S)-3-(4-{[(2S,5S,3R,4R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-3-hydroxypropyl]-1-phenyl-4-(4-fluorophenyl)azetidine-2-one

[0056] (40)(4R*,3R*)-4-(4-{[(5S,2R,3R,4R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-3-[3-(4-fluorophenyl)propyl]-1-(4-fluorophenyl)azetidine-2-one

[0057] (41)3-((3S)-3-Hydroxy-3-phenylpropyl)(4S,3R)-4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-1-phenylazetidine-2-one

[0058] (42)4-[3-((3S)-3-(4-Fluorophenyl)-3-hydroxypropyl](4S,3R)-4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-2-oxoazetidinyl]benzoicacid ethyl ester

[0059] (43)4-(4-{[(5S,2R,3R,4R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)(4S,3R)-1-(4-methylphenyl)-3-[3-(4-fluorophenoxy)ethyl]azetidine-2-one

[0060] (44)3-(3-Phenylpropyl)(4S,3R)-4-(4-{[(5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-1-phenylazetidine-2-one

[0061] (45)(4S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]ethene}phenyl)-1-(4-fluorophenyl)azetidine-2-one

[0062] (46)(4S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]4-(4-([(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]ethyl}phenyl)-1-(4-fluorophenyl)azetidine-2-one

[0063] (47)(4S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]-1-propen-3-yl}phenyl-1-(4-fluorophenyl)azetidine-2-one

[0064] (48)(4S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]propyl}phenyl-1-(4-fluorophenyl)azetidine-2-one

[0065] (49)3-((3S)-(4-[(2S,5S,3R,4R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]phenyl}-3-hydroxypropyl)(4S,3R)-1,4-bis(4-fluorophenyl)azetidine-2-one

[0066] (50)(4S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methoxypropyl-3-yl}phenyl-1-(4-fluorophenyl)azetidine-2-one

[0067] (51)(4S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methoxy-2-propen-3-yl}phenyl-1-(4-fluorophenyl)azetidine-2-one

[0068] (52)(4S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]-1-buten-4-yl}phenyl-1-(4-fluorophenyl)azetidine-2-one

[0069] (53)(4S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]butyl}phenyl-1-(4-fluorophenyl)azetidine-2-one

[0070] (54)(4S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]-1-penten-5-yl}phenyl-1-(4-fluorophenyl)azetidine-2-one

[0071] (55)(4S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]pentyl}phenyl-1-(4-fluorophenyl)azetidine-2-one

[0072] (56)(4S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]ethyl-2-yl)phenyl-1-phenylazetidine-2-one

[0073] (57)(4S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]ethyl-2-yl}phenyl-1-(4-methylphenyl)azetidine-2-one

[0074] (58)(4S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(carboxyl)perhydro-2H-pyran-2-yl]ethyl-2-yl}phenyl-1-(phenyl)azetidine-2-one

[0075] Typical preparation of the compounds according to the inventionare shown, but they are not limited to these compounds. The compoundsshowing the specific rotation are either prepared as the opticallyactive compound or separated as optically active compounds by thesuitable methods and determined the specific rotation.

[0076] The compound of general formula (I) can be obtained as follows.No. Structure mp (° C.) [α _(D) ²⁵/(C, Solv.) 1

89-90 −40.4 (C = 0.5, MeOH) 2

110-112 −33.2 (C = 0.5, MeOH) 3

56-58 4

76-78 5

73-75 6

60-62 7

80-82 −46.7 (C = 0.3, MeOH) 8

56-58 9

84-86 −40.4 (C = 0.5, MeOH) 10

60-61 11

74-75 12

65-67 −40.4 (C = 0.5, CHCl₃) 13

64-66 14

61-62 15

64-65 16

73-75 17

105-106 18

73-74 19

170-172 20

76-78 21

161-162 22

115-117 −71.3 (C = 0.3, MeOH) 23

104-106 −110  (C = 0.5, MeOH) 24

102-104 −58.0 (C = 0.3, MeOH) 25

67-69 −62.8 (C = 0.5, MeOH) 26

78-80 −67.2 (C = 0.5, MeOH) 27

104-106 −26.0 (C = 0.5, MeOH) 28

86-88 −35.7 (C = 0.6, MeOH) 29

148-150 −122.0 (C = 0.3, MeOH) 30

102-104 −52.0 (C = 0.3, MeOH) 31

97-99 32

liq −39.3 (C = 0.8, MeOH) 33

82-84 −47.6 (C = 0.5, MeOH) 34

83-85 35

81-83 36

79-81 37

80-82 38

200-201 −69.3 (C = 0.3, MeOH) 39

126-128  −42.66 (C = 0.3, MeOH) 40

78-80 41

110-112 −67.2 (C = 0.5, MeOH) 42

56-58 −92.0 (C = 0.3, MeOH) 43

96-98 −40.4 (C = 0.5, CHCl₃) 44

84-86 −41.3 (C = 0.3, MeOH) 45

84-86 −64.0 (C = 0.25, MeOH) 46

153-155  −54.66 (C = 0.25, MeOH) 47

72-74 −33.6 (C = 1.0, MeOH) 48

81-83 −21.8 (C = 1.0, MeOH) 49

111-113 −20.0 (C = 0.35, MeOH) 50

61-63 −48.6 (C = 0.14, MeOH) 51

65-67 −42.8 (C = 0.25, MeOH) 52

79-81 −33.2 (C = 1.0, MeOH) 53

81-83 −29.4 (C = 0.5, MeOH) 54

69-71 −38.6 (C = 0.35, MeOH) 55

66-68 −42.9 (C = 0.35, MeOH) 56

82-84 −49.2 (C = 1.0, MeOH) 57

116-118 −76.0 (C = 0.3, MeOH) 58

110-112 −40.3 (C = 0.7, MeOH)

[0077] Method 1

[0078] (1) (a) In case of R₄ is —CH₂— in the compounds of generalformula (I), the compound is prepared by the following reactions.

[0079] The compound (1-2) obtained by a reaction of tetrabenzylglucuronolactone (1-1) with Tebbe reagent (T. V. Rajanbabu et al.,J.Org.Chem. 1986, 51, 5458), is used as a starting material. Thecompound (1-2) is subjected to Suzuki coupling reaction with thecompound (1-3) (C. R. Johnsone et al., Synlett 1997, 1406) followed bydesilylation to yield the compound (1-4).

[0080] (b) The compound (1-5) is obtained by oxidation of the hydroxylgroup of compound (1-4) to obtain the aldehyde compound (1-5).

[0081] (c) The aldehyde compound (1-5) and the amine compound (1-6) arecondensed in the presence of a molecular sieves and p-toluenesulfonicacid to obtain the compound (1-7).

[0082] The imine compound (1-7) and the compound (1-8) are subjected toStaudinger reaction by refluxing in the presence of base to yield aβ-lactam compound. In this reaction, when tri-n-butyl amine is used asthe base, the trans β-lactam compound is obtained. When LDA (lithiumdiisopropyl amide) is used as the base, the cis β-lactam compound isobtained.

[0083] Furthermore, the asymmetric β-lactam compound can be alsoobtained by addition of a chiral ligand in the reaction mixture (A. M.Hafez et al., Org. Lett. 2000, 2(25), 3963-3965). Subsequently, thedebenzylated compound (1-9) is obtained by catalytic hydrogenation.

[0084] (d) The compound (1-10) is obtained by an acetylation of thecompound (1-9).

[0085] (2) In case of R₄ is —CH₂— in the compounds of general formula(I), the compound is prepared by the following reactions.

[0086] The compound (1-11) is reacted with Grignard reagent (1-12) toyield the compound (1-13) (M. F. Wong et al., J. Carbohydr. Chem. 1996,15(6), 763; C. D. Hurd et al., J. Am. Chem. Soc. 1945, 67, 1972; H. Togoet al., Synthesis 1998, 409). Alternatively, the compound (1-11) isreacted with Grignard reagent (1-12) followed by dehydroxylation withtriethylsilyl hydride. The generated hydroxyl group is converted to aleaving group such as tosyl group or halogen and the resulting compoundis reacted with base to yield the olefin compound. Then the compound(1-13) is obtianed by hydrogenation of the olefin compound. The compound(1-13) is converted to Grignard reagent with magnesium metal and reactedwith DMF (dimethylformamide) to yield the compound (1-14). The compound(1-15) is obtained by the reaction of Grignard reagent of the compound(1-13) with dry-ice (CO₂).

[0087] The compound (1-14) and the compound (1-15) which are obtained asabove mentioned are the synthetic intermediates of the general formula(I) according to the Method 1-(1)-(c) and (d).

[0088] Method 2

[0089] (1) In case of R₄ is a directly connected bond in the compoundsof general formula (I), the compound is prepared by the followingreactions.

[0090] Tetrabenzylglucuronolactone (1-1) is reacted with the compound(2-1) followed by the reaction with Et₃SiH and BF₃.Et₂O to provide thecompound (2-2) (J. M. Lancelin et al., Tetrahedron Lett. 1983, 24,4833). The compound (2-2) is the synthetic intermediates of the generalformula (I) according to the method 1-(1)-(b), (c), and (d).

[0091] (2) In case of R₄ is a directly connected bond in the compoundsof general formula (I), the compound is prepared by the followingreactions.

[0092] The compound (2-4) is obtained by the reaction of the compound(1-11) with Grignard reagents (2-3) (F. Marquez et al., An. Quim., Ser.C. 1983, 79(3), 428).

[0093] The compound (1-14) is obtained by conversion of the methyl groupof the compound (2-4) to the aldehyde compound (P. S. Portoghese et al.,J. Med. Chem. 2000, 43, 2489).

[0094] The compound (2-2) is obtained by reduction of the compound(1-14) with NaBH₄.

[0095] Method 3

[0096] (1) In case of R₄ is —OCH₂— in the compounds of general formula(1), the compound is prepared by the following reactions.

[0097] (a) The compound (3-1) prepared by the known method (D. Zhai etal., J.Am.Chem. Soc. 1988, 110, 2501.; P. Allevi et al., J. Carbohydr.Chem. 1993, 12(2), 209) is subjected to Mitsunobu reaction with thecompound (3-2) to provide the compound (3-3).

[0098] (b) The compound (3-4) is obtained by reduction of themethylester group of the compound (3-3) to the alcohol group withLiAlH₄.

[0099] The compound (3-4) is the synthetic intermediates of the generalformula (I) according to the method 1-(1)-(b), (c), and (d).

[0100] Method 4

[0101] In case of that one of A₁, A₃, and A₄ is the following compoundin the compounds of general formula (I), the compound is prepared by thefollowing reactions.

[0102] The compound (4-1) is reacted with 2-bromoisolactic acidalkylester (4-2) in the presence of K₂CO₃ followed by hydrogenation toyield the compound of general formula (I). Alternatively, the compound(4-3) is obtained by hydrolysis with lithium hydroxide and followed bythe deprotection to provide the compound of general formula (I).

[0103] Method 5

[0104] In case of R₂ is —CO₂H in the compounds of general formula (I),the compound is prepared by the following reactions.

[0105] The compound (5-1) is oxidazed with TEMPO(2,2,6,6-tetramethyl-1-piperidinyloxy, free radical) to yield thecompound (5-2).

[0106] Method 6

[0107] The compound (6-3) is obtained by the reaction of the compound(6-1) and (6-2). The compound (6-3) is oxidazed to the sulfone compoundfollowed by Ramberg-Bäcklund reaction (P. S. Belica et. al., TetrahedronLett. 1998, 39, 8225.; F. K. Griffin et al., Tetrahedron Lett. 1998, 39,8179) to afford the compound (6-4). The compound (6-4) is hydrogenatedfollowed by a reaction with TBAF to provide the compound (1-4). Thecompound (1-4) can be used as synthetic materials to obtain generalformula (I) according to the method 1.

[0108] Method 7

[0109] (1) In case of R₃ is —OH— and —OC(O)R₁ in the compounds ofgeneral formula (I), the compounds are prepared by the followingreactions.

[0110] The compound (7-3) is obtained by glycosidation of the compound(7-1) with the compound (1-11) in the presence of Lewis acid (BF₃.Et₂O,SnCl₄, AgOTf—Cp₂HfCl₂, etc) (R. R. Schmidt et al., Synthesis 1993, 325).The reaction proceed in 2 steps, first step is O-glycosidation andsecond step is O-glycoside rearrengment to C-glycoside. Futhermore, thecompound (7-3) can be converted to the compound (7-4) by esterificationof the phenolic hydroxyl group. The compound (7-3) and (7-4) can be usedas the synthetic materials to obtain general formula (I) according tothe method 1 and 3.

[0111] (2) In case of R₃ is —OH— and —OC(O)R₁ in the compounds ofgeneral formula (I), the compounds are prepared by the followingreactions.

[0112] The compound (7-6) obtained by the same procedure of method 7-(1)is deprotected to obtain the compound (7-7). One of the hydroxyl groupof the compound is triflated, followed by a reaction of carbonemonooxide to give the compound (7-3) (R. E. Dolle et al, Chem. Commun.1987, 904). The compound (7-3) is used as the starting material ofgeneral formula (I) according to the method 7-(1), 1 and 3.

[0113] The compound (7-3) is also obtained by the same coupling reactionof the compound (7-11) with the compound (1-11) to obtain the compound(7-12) followed by Haloform reaction of the acetyl group to obtain thecompound (7-3) (S. Kajigaeshi et al., Synthesis 1985, 674).

[0114] (3) In case of R₃ is —OH— and —OC(O)R₁ in the compounds ofgeneral formula (I), the compounds are prepared by the followingreaction.

[0115] The compound (7-10) is obtained by the aryl C-glycosidation ofthe compound (7-9) according to the method 7 (1). The compound (7-10) isused as a starting material of general formula (I) according to themethod 8.

[0116] Method 8

[0117] The preparative methods of the optically active compounds (I).

[0118] (a) Benzylation of the hydroxy group of D-p-hydroxyphenylglycine(8-1) provides the compound (8-2) using E. Wunsch's method (Chem. Ber.1958, 91, 543).

[0119] The compound (8-3) is obtained by the protection of the aminogroup of the compound (8-2) with Boc group.

[0120] The compound (8-3) is converted to the compound (8-4) byhomologation (W. W. Ogilvie et al., Bioorg. Med. Chem. 1999, 7, 1521).Then, the compound (8-5) is obtained by deprotection of the Boc group ofthe compound (84).

[0121] Cyclization of the compound (8-5) provides the β-lactam (8-6)using W. W. Ogilvie's method (W. W. Obilvie et al., Bioorg. Med. Chem.1999, 7, 1521).

[0122] The compound (8-5) is also obtained by following method as theoptically active compound.

[0123] Namely, the compound (8-9) is obtained by the reaction of thecompound (8-7) with the optically active amino acid derivatives (8-8) inthe presence of acid catalyst. The compound (8-9) is directly reduced tothe compound (8-11). The compound (8-11) is also obtianed by a reductionof olefin (ex. NaHB(OAc)₃, NaBH₄) and treated with strong acid (ex.HCO₂H, Et₃SiH) (C. Cimarell et al., J.Org.Chem. 1996, 61, 5557) orhydrogenolysis. The compound (8-11) provides the compound (8-5) by anester exchange reaction with BnOH. The compound (8-5) can be convertedto the compound (8-6) by the same method as above mentioned.

[0124] The β-lactam compound (8-6) is N-alkylated by D. M. T. Chan'smethod (Tetrahedron Lett. 1998, 39, 2933), followed by debenzylation toafford the compound (8-12).

[0125] The compound (8-13) is obtained by Suzuki coupling reaction ofthe compound (8-12) and the glucose derivatives (1-2) according to C. R.Johnson's method (C. R. Johnson et al., synlett 1997, 1406).

[0126] The compound (8-13) is reacted with LDA, followed by C-alkylationwith methyl acrylate to provide the compound (8-14).

[0127] The convention of ester group of the compound (8-14) to the acidchloride, and coupling with the compound (8-15) using Negishi's methodand obtained the compound (8-16).

[0128] The compound (8-16) is debenzylated to the compound (8-17) andfollowed by asymmetric reduction of the ketone group of the compound(8-17) by E. J. Corey's method (E. J. Corey et al., J. Am. Chem. Soc.1987, 109, 7925).

[0129] (b) The compound (8-13) is reacted with LDA, followed by thereaction with the compound (8-20) to provide the compound (8-21). Thecompound (8-22) is obtained by hydrogenation of the compound (8-21).

[0130] In case of A₁ in the general formula (I) is the followingcompound,

[0131] for example, according to the method 8, the compound 39 isprepared from the following compound (8-23) which correspond to thecompound (8-15).

[0132] In case of A₄ in the general formula (I) is the followingcompound,

[0133] for example, according to the method 8, the compound 38 isprepared from the following compound (8-24) which correspond to thecompound (8-12).

[0134] The compound (8-25) is also obtained by enzymatic separation of aracemic compound (S. J. Faulconbridge et al., TetrahedronLett.,2000,41,2679). The compound (8-25) can be converted to generalformula (2) by Suzuki coupling as above mentioned.

[0135] Method 9

[0136] The preparative method of the optically active compounds (II).

[0137] The compound (9-1) is condenced with the compound (9-2) toprovide the compound (9-3) by K. Tomioka's method (K. Tomioka et al., J.Chem. Soc., Chem. Commun. 1999, 715). The compound of general formula(I) is obtained by deprotection of the compound (9-3). The compound(9-3) is also obtained by the reaction of the silyl enol ether withLewis acid instead of the compound (9-1).

[0138] Method 10

[0139] The preparative method of the optically active compounds (III).

[0140] The compound (10-1) is condenced with the compound (9-2) toprovide the compound (10-4) by E. J. Corey's method (E. J. Corey et al.,Tetrahedron Lett. 1991, 32, 5287). The compound of general formula (I)is obtained by deprotection of the compound (10-4).

[0141] Method 11

[0142] The preparative method of the optically active compounds (IV).

[0143] (R)-(+)-2,10-camphorsultam (11-1) is reacted with acid chloride(11-2) and obtained the compound (11-3). The compound (11-5) is obtainedby coupling reaction of the compound (11-3) and the compound (114) inthe presence of Lewis acids (TiCl₄, BF₃.OEt₂). The compound (11-5) isreacted with BSA, followed by reaction with TBAF (n-tetrabutylammoniumfluoride) to afford the β-lactam compound (11-6).

[0144] The obtained compound (11-6) is converted to the compound (8-15)by the same method as the method 8.

[0145] The compound (11-6) can be used as the starting material of thecompound of general formula (I), according to the method 8. Furthermore,when the compound (11-7) is used instead of the compound (114), thecompound (11-8) which correspond to the compound (11-6) can be obtainedby the same method.

[0146] The compound (11-9) can be obtained from the compound (11-8) bythe same method as the method 7.

[0147] The compound (11-9) can be used as the starting material ofgeneral formula (I), according to the method 8.

[0148] Method 12

[0149] The compound (11-6) is subjected to Heck reaction with thecompound (12-1) prepared by reported method (M. Yokoyama et al.,Synthesis 1998, 409) and obtain the compound (12-2). (R. F. Heck et al.,J. Am. Chem. Soc. 1968, 90, 5518) The compound (12-2) can be used as thestarting material of general formula (1), according to the method 8.

[0150] The compound (12-3) is obtained by hydrogenation of the compound(12-2). The compound (12-3) can be used as the starting material ofgeneral formula (1), according to the method 8.

[0151] Method 13

[0152] C-glycosidation of the compound (13-1) with the compound (1-11)(R₆ is -Me, —Br, or —CH₂OTBS) provides the compound (13-2) in thepresence of Lewis acid (BF₃.OEt₂, ZnCl₂, AgOTf). (K. C. Nicolaou et al.,J. Chem. Soc., Chem. Comm. 1984, 1153) The R₆ of the compound (13-2) isconverted to aldehyde by the same method as the method 1-(1)-(6), 1-(2),or 2-(2). The obtained compound can be used as the starting material ofgeneral formula (1), according to the method 1.

[0153] Method 14

[0154] The compound (14-1) is subjected to the coupling reaction such asSuzuki coupling reaction and Grignard reaction (Angew. Chem. Int. Ed.Engl. 2000, 4415), or alkylation in the presence of base. Afterdeprotection, the compound (14-3) is obtained.

[0155] Method 15

[0156] The compound (15-1) which is prepared by L. Dheilly's method (L.Dheilly et al., Carbohydr. Res. 1992, 224, 301), is converted to thecompound (15-2) by reduction and halogenation. The compound (15-2) istransformed to the organometalic reagents (Grignard reagent, organozincreagent), followed by coupling reaction with the compound (15-3) in thepresence of palladium or nickel catalysts. Then, the compound (15-4) isobtained by cyclization.

[0157] Method 16

[0158] The compound (16-1) can be obtained by Heck reaction using thecompound (12-1) and the compound (15-3) as same as the method 12. Thecompound (16-1) is converted to the genaral formula (I) according to themethod 17.

[0159] Method 17

[0160] The compound (17-1) is treated with lithium hydroxide to removecamphorsultam and obtained the compound (17-2). (The camphorsultam canbe collected and reused.) Then, the compound (17-2) is cyclized withPOCl₃ in the solvent such as dichloromethane or dichloroethane to yieldthe general formula (I). The compound of general formula (I) is alsoobtained by using the condensing reagents such as DCC(1,3-Dicyclohexycarbodiimide) or DEPC (Diethylphosphorylcyanide) indichloromethane or DMF in the presence of base. Further the compound ofgeneral formula (I) is also obtained by using Mitsunobu reagent, DEAD(Diethylazodicarboxylate) or DIAD (Diisopropylazodicarboxylate) withBu₃P or Ph₃P or by reacting with (PyS)₂ or after reacting with2,6-dichloro-benzoyl chloride or 2,4,6-trichloro benzoyl chloride in thepresence of NaH and treating with base like NaOH solution and obtainedthe general formula (I).

[0161] Or the compound (17-2) is esterified to the compound (17-3),followed by reaction of base such as LDA, LiHMDS (lithiumbis(trimethylsilyl)amide), NaHMDS (sodium bis(trimethylsilyl)amide),NaH, t-BuOK in solvent such as THF to yield the general formula (I). Thegeneral formula (I) is also obtained by a reaction of Grignard reagentsuch as EtMgBr, t-BuMgBr with compound (17-3). Applying the samereaction to the compound (17-1), the compound of the general formula (I)is obtained.

[0162] Method 18

[0163] The compound (18-2) is obtained by SeO₂ oxidation of the compound(18-4) or Pd(OAc)₂-benzquinone-HClO₄ oxidation of the compound (184),then an asymmetric reduction of the ketone group of compound (18-2)provided to the compound (18-3). The compound (18-3) are also obtainedby hydroboration of the compound (18-4). When a chiral borane reductantis used, the hydroboration proceeds stereoselectively.

[0164] In the formula which are discribed between method 1 and method18, A₁, A₂, A₄, R₃, R₄, p, q, r, and Z are as mentioned above, and R₆ is—CH═CH₂, —CH₂OH. k is integer of ≧1, l is 0 or an integer of ≧1, k+l isan integer of ≦10.

[0165] Method 19

[0166] The compound (19-2) is obtained by asymmetric reduction of thecompound (19-1). As asymmetric reductions, the transition metalcatalysts are used (R. Noyori et al., J.Am.Chem.Soc. 1987, 109, 5856.).After the hydroxy group of the compound (19-2) is converted to a leavinggroup, the resulting compound is cyclized to obtain the compound(119-3). Or directly the compound (119-3) is obtained by Mitsunobureaction of the compound (19-2). The compound (19-3) is subjected toHeck reaction with the compound (12-1), then the generated double bondis hydrogenated to give the compound (19-4). Or the compound (19-3) issubjected to Negishi coupling reaction (T. Hayashi et al.,J.Am.Chem.Soc. 1984, 106, 158-163.; A. Saiga et al., Tetrahedron Lett.2000, 41, 4629-4632; C. Dai et al., J.Am.Chem.Soc., 2001, 123,2719-2724) with the compound (19-5) to obtain the compound (19-4). Thecompound (19-4) can be used the synthetic material of the generalformula (I) according to example 8.

[0167] Method 20

[0168] Synthesis of Compound (19-3)

[0169] The imine compound (20-1) is subjected to asymmetric reduction toobtain the compound (20-2) according to example 19. The ester group ofthe compound (20-2) is hydrolyzed to the corresponding carboxylic acidcompound and the obtained carboxylic acid is subject to β-lactamisationby using the condensing reagent (for example DCC) to give the compound(19-3). The compound (19-3) is also obtained by β-lactamisation of thecompound (20-2) using EtNgBr for example. The compound (19-3) can beused the synthetic material of the general formula (I) according toexample 19.

[0170] Method 21

[0171] Synthesis of Compound (21-10)

[0172] The compound (19-1) is reacted with an base, followed by additionof the compound (21-1) to give the compound (21-2). The compound (21-2)is converted to the compound (21-4) by asymmetric reduction or to thecompound (21-5) by reaction with the compound (21-3).

[0173] The compound (21-4) is reacted with the compound (21-3) to affordthe compound (21-6). Subsequently, the compound (21-6) is coupled withthe sugar compound (12-1 or 19-5) to give the compound (21-8), then theβ-lactam compound (21-10) is obtained.

[0174] On the other hand, after the compound (21-7) is obtained byasymmetric reduction of the compound (21-5) and the obtained compound(21-7) is coupled with the sugar compound (12-1 or 19-5) to afford thecompound (21-9). The compound (21-10) is also obtained byβ-lactamisation of the compound (21-9). The compound (21-10) can be thesynthetic material of the general formula (I).

[0175] [Hypocholesterolemic Agents Using the HypercholesterolemicHamster]

[0176] Hamsters were derived into groups with 3 animals per group andfed a 0.5%-cholesterol containing CE-2 diet (CLEA Japan Inc.) for 4 or 7days. The normal dietary group were fed a standard CE-2 during theexperiment. Each compound or vehicle (0.2 mL of corn oil) per 100 g bodyweight was orally administered daily for 4 or 7 days from the day thathigh-cholesterol diet was started. At 20 hr after the finaladministration, blood samples were collected from the abdominal aorta ofnon-fasted animals under anesthesia with diethylether. Serum cholesterolwas measured by enzymatic method using cholesterol E-test wako (WakoPure Chemical Industries). Activity of the test compounds is expressedas percent reduction of the test compound on the basis of comparisonwith rised total cholesterol treated only withno-treatment-high-cholesterol diet. The test compounds with the opticalrotation value in the compounds 1-58 were evaluated as the chiralcompounds. The result is shown in the next table. Each value in thetable shows the changed percent and the negative value indicates thepositive hypocholesterolemic action. TABLE 13 Test Comp. Serumcholesterol No. (mg/kg) Dosage day (%) 2 3 7 −120 13 20 4 −28 15 20 4−21 23 3 7 −177 24 3 7 −156 28 3 7 −130 33 3 4 −67 38 10 4 −2 45 3 4−136 46 3 4 −147 49 10 4 −55 56 0.3 4 −84.0 57 0.3 4 −81.3

[0177] [Biological Stability Test]

[0178] To evaluate the stability of C-glycoside, the biologicalstability of C-allyl derivative (A) and O-allyl derivative (B) againstto α-N-acetyl-D-galactosaminidase as glycosidase ware compared accordingto Mark von Itzstein's method (Org.Lett., 1999,1,443-446).

[0179] [Chemical Formula 69]

[0180] enzyme; α-N-acetyl galactosaminidase 0.32 unit (1.69 unit/mL 0.1%BSA containing 0.5M sodium citrate buffer)

[0181] solvent; citric acid buffer (pD=3) 0.6 mL

[0182] temperature; 35° C.

[0183] procedure; Substrate (2 mg) was dissolved in citric acid buffer(0.6 mL) and α-N-acetyl galactosaminidase (0.32 unit) was added. NMRspectrum was determined in every constant time and the content of theremaining substrates were determined.

[0184] The result of the remaining substrates were shown in table 14.TABLE 14 time substrate 2 4 6 8 10 12 18 24 B 89 79 68 57 50 45 40 22 A100 100 100 100 100 100 100 100

[0185] From the above results, 78% of O-allyl derivative (B) was clearlyhydrolyzed after 24 h. C-allyl derivative (A), replaced ether bond toC—C bond, was unaffected by enzyme as expected and the formation of thedegradation was not observed after 24 h.

EXAMPLE

[0186] The following examples are provided only for the purpose of thepreparation of the compound and not restrict the disclosed invention.

[0187] Reference 1

[0188]4-(4-{[(5S,2R,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-perhydro-2H-pyran-2-yl-]methyl)phenyl)(4S*,3S*)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)propyl]azetidine-2-on

[0189] Reference 1-a

[0190] Synthesis of Compound (1-4)

[0191] A 50 mL of 9-BBN (0.5 M tetrahydrofuran solution) was added to asolution of the compound (1-2) (5.37 g) in tetrahydrofuran (70 mL) andthe mixture was refluxed for 5 hr, cooled to room temperature and 3 Mpotassium phosphate (10 mL) was added to the mixture at room temperaturefor 15 min. To the reaction mixture was added a solution of4-(tert-butyldimethyl-silyloxymethyl)bromo-benzene (3.01 g) and PdCl₂(dppf) (0.73 g) in N,N-dimethylformamide (100 mL). The mixture wasstirred for 18 hr. The organic layer was washed with brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Tothe residue was added tetrabutylammonium fluoride (1.0 M tetrahydrofuransolution) (15 mL). The mixture was stirred for 3 hr and extracted withethyl acetate. The organic layer was washed with brine, dried overanhydrous sodium sulfate, and concentrated. The residue was purified bysilica gel column chromatography (ethyl acetate/hexane=1/2) to give 3.58g (2 steps, 56%) of the compound (1-4).

[0192] Mass (ESI) m/z: 662 (M+H₂O)⁺

[0193] IR (KBr): 3430 cm⁻¹

[0194]¹H-NMR (CDCl₃): 2.71 (d,J=8.8, 13.2 Hz), 3.13(d,J=2.4, 14.2 Hz),3.32˜3.36(m,2H), 3.45˜3.50(m,1H), 3.60˜3.74(m,4H), 4.48˜4.68(m,6H),4.80˜4.95(m,4H), 7.18˜7.37(m,24H)

[0195] Reference 1-b

[0196] Synthesis of Compound (1-5)

[0197] To a solution of the compound (14) (3.6 g) in chloroform (22.0mL) was added manganese dioxide (9.65 g) and the mixture was refluxedfor 2 hr, and cooled to room temperature. The mixture was filteredthrough a pad of Celite and evaporated to gave 3.46 g (97%) of thecompound (1-5) as a colorless crystal.

[0198] Mass (ESI) m/z: 660 (M+H₂O)⁺

[0199] IR (KBr): 1692 cm⁻¹

[0200]¹H-NMR(CDCl₃): 2.77(d,J=8.8, 14.2 Hz), 3.16˜3.20(m,1H),3.32˜3.36(m,2H), 3.49(dt,J=2.0, 9.3 Hz), 3.61˜3.66(m,3H), 3.72(t,J=8.8Hz), 4.46˜4.67(m,4H), 4.81˜4.97(m,4H), 7.18˜7.41(m,22H), 7.74(d,J=8.3Hz), 9.95(s,1H)

Example 1

[0201] (I) To a solution of the compound (1-5) (3.46 g) in toluene (54.0mL) were added molecular sieve (3.46 g), a catalytic ammount ofp-toluenesulfonic acid and p-fluoroaniline (0.61 mL). The mixture wasrefluxed for 1.5 hr and filtered. The solvent was removed under reducedpressure and the residue was subjected to the next reaction withoutpurification.

[0202] (II) To the solution of the compound obtained above in toluene(54.0 mL) were added tributylamine (5.1 mL) and5-(4-fluorophenyl)pentanoyl chloride (1.16 g). After the mixture wasrefluxed for 15 hr and 1 N hydrochloric acid (15 mL) was added to themixture and the mixture was stirred for 15 min. The organic layer wasseparated and washed with saturated sodium bicarbonate solution, brineand dried over anhydrous sodium sulfate and concentrated. The residuewas subjected to the next reaction without purification.

[0203] (III) The solution of the compound obtained above inmethanol-tetrahydrofuran (5/1) (6 mL) was hydrogenated at roomtemperature for 5 hr in the presence of 10% palladium on carbon (200mg). After removal of the catalyst and the reaction mixture wasevaporated and the residue was chromatographed on silica gel(chloroform/methanol=10/1) to give 64 mg (26%) of the compound 2.

[0204] Mass (ESI) m/z: 554 (M+H)⁺

[0205] IR (KBr): 3376, 1737, 1503, 1218 cm⁻¹

[0206]¹H-NMR (CD₃OD):1.82˜1.98(m,4H), 2.65˜2.78(m,3H), 3.09˜3.39(m,7H),3.64(d,J=5.4, 12.2 Hz), 3.77˜3.81(m,1H), 4.94˜4.98(m,1H),6.98˜7.05(m,4H), 7.18˜7.22(m,2H), 7.30˜7.33(m,4H), 7.38(d,J=7.8 Hz,2H)

Example 2

[0207] Synthesis of Compound 3

[0208]4-(4-([(5S,2R,3R,4R,6R)-3,4,5-triacetoxy-6-(acetoxymethyl)-perhydro-2H-pyrane-2-yl]methyl}phenyl)-(4S*,3S*)-1-(4-fluorophenyl)-3-[3-(4-fluorofenyl)propyl]azetidine-2-one

[0209] To a solution of the compound 2 (600 mg) in dichloromethane (11.0mL) were added triethylamine (0.77 mL), acetic anhydride (0.49 mL) and acatalytic ammount of 4-dimethylaminopyridine. The mixture was stirred atroom temperature for 16 hr. The organic layer was washed with brine,dried over anhydrous sodium sulfate and concentrated. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane=1/2)to give 600 mg (77%) of the compound 3.

[0210] Mass (ESI) m/z: 722 (M+H)⁺

[0211] IR (KBr): 1749, 1506, 1380, 1221, 1029 cm⁻¹

[0212]¹H-NMR (CDCl₃): 1.82˜1.84(m,4H), 1.93(s,3H), 1.97(s,1.5H),1.98(s,1.5H), 1.99(s,1.5H), 2.00(s,1.5H), 2.02(s,3H), 2.61˜2.64(m,2H),2.79˜2.82(m,2H), 3.07˜3.08(m,1H), 3.56˜3.69(m,2H), 4.02˜4.23(m,2H),4.58(d,J=2.4 Hz), 4.89˜4.95(m,1H), 5.03(t,J=9.3 Hz), 5.17(t, J=9.3 Hz),6.90˜7.007(m,4H), 7.08˜7.12(m,2H), 7.18˜7.24(m,6H)

[0213] Reference 2

[0214] Synthesis of Compound (2-2)

[0215] 4-(2,3,4,6-tetra-o-benzyl-β-D-glucopyranosyl)benzyl Alcohol

[0216] To 7.31 g of tetrabenzylgluconolactone was added dropwise at −78°C. the lithium anion, prepared from 6.66 g ofp-(tert-butyldiphenylsilyloxymethyl)bromobenzene and 10 mL of n-butyllithium (1.57 M hexane solution) at −78° C. The mixture was stirred for2 hr and extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous sodium sulfate and concentrated. The residuewas subjected to the next reaction without purification. To a solutionof the compound obtained above in dichloromethane (26 mL) were addedtriethylsilane (0.82 mL) and borontrifluoride-diethylether complex (0.33mL) at −50° C. The mixture was stirred for 1.5 hr. Sodium bicarbonatesolution was added. The mixture was stirred for 1 hr, and then it wasextracted with ether. The organic layer was washed with brine, driedover anhydrous sodium sulfate, and concentrated. The residue waspurified by silica gel column chromatography to give 1.48 g (15%) of thecompound (2-2).

[0217] IR (KBr): 3388, 1452, 1362, 1210, 1068, 1026 cm⁻¹

[0218]¹H-NMR (CDCl₃): 3.49˜3.81(m,4H), 4.04˜4.96(m,13H),6.92˜6.95(m,2H), 7.09˜7.76(m, 2H)

[0219] Reference 3-a

[0220] 4-(2,3,4,6-tetra-o-benzyl-β-D-glucopyranosyl)methoxy Benzoic AcidMethyl Ester

[0221] To a solution of the compound (3-1) (555 mg), methyl p-hydroxybenzoate (153 mg) and triphenylphosphine (394 mg) in tetrahydrofuran(5.0 mL) was added diisopropylazodicarboxylate (0.3 mL). The mixture wasstirred for 22 hr and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethylacetate/hexane=1/3) to give 180 mg (26%) of the compound (3-a).

[0222] IR (neat): 1713, 1605, 1434, 1359, 1248, 1164 cm⁻¹

[0223]¹H-NMR (CDCl₃):3.49˜3.77(m,7H), 3.89(s,3H), 4.07˜4.11(m,1H),4.19˜4.22(m,1H), 4.51˜4.60(m,4H), 4.82˜4.89(m,2H), 4.94(s,2H),6.87(d,J=8.8 Hz,2H), 7.15˜7.36(m,20H), 7.96(d,J=8.8 Hz,2H)

[0224] Reference 3-b

[0225] 4-(2,3,4,6-tetra-o-benzyl-β-D-glucopyranosyl)methoxy BenzylAlcohol

[0226] To a suspension of 10 mg of lithium aluminiumhydride in 5 mL ofether was added 180 mg of the compound (3-a) in 5 mL of ether at 0° C.After the mixture was stirred at room temperature for 15 min, water (2.0mL) and 15% sodium hydroxide solution (0.5 mL) were added and theresulting suspension was filtered through a pad of Celite. After removalof the solvent, the residue was purified by silica gel columnchromatography (ethyl acetate/hexane=1/1) to give 160 mg (93%) of thecompound (3-b).

[0227] Mass (ESI) m/z: 684 (M+H+Na)⁺

[0228] IR (neat): 3442 cm⁻¹

[0229]¹H-NMR (CDCl₃): 1.56(s,1H), 3.49˜3.53(m,1H), 3.60˜3.77(m,6H),4.08˜4.12(m,1H), 4.20˜4.23(m,1H), 4.52˜4.61(m,6H), 4.85(ABq,J=11.2Hz,2H), 4.93(s,2H), 6.88(d,J=8.8 Hz,2H), 7.15˜7.36(m,22H)

[0230] Reference 3-c

[0231] Synthesis of Compound (1-14)

[0232] 4-(2,3,4,6-tetra-o-benzyl-β-D-glucopyranosyl)benzaldehyde

[0233] (I) To a solution of the4-(2,3,4,6-tetra-o-benzyl-β-D-glucopyranosyl)toluene (0.3 g) in carbontetrachloride (3 mL) were added NBS (0.9 mg) and benzoylperoxide (0.05g). The mixture was refluxed for 2 hr. After cooling to roomtemperature, ether (30 mL) was added to the mixture. The resulting saltswere filtered off by suction. The filtrate was concentrated and theresidue was purified by silica gel column chromatography (ethylacetate/hexane=1/8).

[0234] (II) To a solution of bromide (224 mg) obtained above indimethylsulfoxide (3 mL) was added sodium bicarbonate (45 mg). After themixture was stirred at room temperature for 1 hr and 100° C. for 4 hr,the mixture was extracted with ethyl acetate (30 mL). The organic layerwas washed with brine, and dried over anhydrous sodium sulfate. Removalof the solvent under reduced pressure gave the compound (1-14) (2 steps26%).

[0235] Mass (m/z): 436 (M⁺), 394, 307, 273, 245, 214, 163, 135, 105, 77,51 (BP)

[0236] IR (neat): 2914, 1641, 1437, 1257, 1017, 954, 708 cm⁻¹

[0237]¹H-NMR(CDCl₂,400 MHz)δ: 1.96, 1.97, 2.06(12H,each,s),3.75˜5.40(7H,m), 7.96, 8.02(4H, ABq), 10.06(1H,s)

Example 3

[0238]2-(4-[4-{(5S,2R,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethy)-perhydro-2H-pyran-2-yl}methyl]phenyl)(4S*,3R*)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)propyl]-2-oxazetidineyl)phenoxy-2-methylpropanoic Acid

[0239] (I) To a solution of the compound (4-4) (3.19 g) in acetone (22.0mL) were added ethyl 2-bromo-2-methylpropionate (0.77 mL) and potassiumcarbonate (0.97 g). The mixtue was refluxed for 40 hr, filtered, andconcentrated. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane=1/3).

[0240] (II) A solution of the compound 18 (2.93 g) obtained above inethanol-tetrahydrofuran (1/1) (40 mL) was hydrogenated at roomtemperature for 3 hr in the presence of 10% palladium on carbon (0.3 g).After removal of the catalyst, the filtrate was evaporated. The residuewas purified by silica gel column chromatography(chloroform/methanol=10/1) to give 1.21 g (2 steps 51.8%) of thecompound 18.

[0241] To a solution of the compound 18 (400 mg) intetrahydrofuran-water (5/1) (3 mL) was added lithium hydroxide (50 mg).The mixture was stirred at room temperature for 8 hr and 1 Nhydrochloric acid was added to adjust to pH 3. The mixture was extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous sodium sulfate and concentrated. The residue was purified bysilica gel column chromatography (chloroform/methanol=5/1) to give 377mg (3 steps 51.0%) of the compound 19.

[0242] Mass (ESI) m/z: 636 (M−H)⁻

[0243] IR (KBr): 3400, 1722, 1503 cm⁻¹

[0244]¹H-NMR(CD₃OD): 1.53(s,6H), 1.81˜1.95(m,4H), 2.65˜2.68(m,2H),2.72˜2.78(m,1H), 3.09˜3.41(m,7H), 3.62˜3.66(m,1H), 3.77˜3.82(m,1H),4.81(d,J=2.0 Hz,1H), 6.85(d,J=9.3 Hz, 2H), 6.97˜7.02(m,2H),7.18˜7.22(m,4H), 7.30(d,J=7.8 Hz,1H), 7.38(d,J=8.3 Hz,2H)

Example 4

[0245] Synthesis of Compound 17

[0246]6-[(4-{(2S*,3S*)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)propyl]-4-oxoazetidine-2-yl}(2S,3S,4R,5R,6R)-3,4,5-trihydroxyperhydro-2H-pyran-2-carboxylicAcid

[0247] To a mixture of the compound 2 (300 mg),2,2,6,6-tetramethyl-1-piperodinyloxy, free radical (10 mg) and potassiumbromide (10 mg) in acetonitrile (6.6 mL) were added saturated sodiumbicarbonate solution (6.6 mL) and sodium hypochlorite (6.6 mL). Themixture was stirred at room temperature for 3 hr and then extracted withethyl acetate. The organic layer was washed with brine, dried overanhydrous sodium sulfate and concentrated. The residue was purified bysilica gel column chromatography (chloroform/methanol=10/1) to give 90mg (29.4%) of the compound 17.

[0248] Mass (ESI) m/z: 566 (M−H)⁻

[0249] IR (KBr): 3388, 1737, 1509 cm⁻¹

[0250]¹H-NMR (CD₃OD): 1.82˜1.97(m,4H), 2.65˜2.68(m,2H), 2.71˜2.79(m,1H),3.12˜3.24(m, 3H), 3.34˜3.52(m,3H), 3.62˜3.68(m,1H), 4.84(d,J=2.0 Hz,1H),6.98˜7.05(m,4H), 7.18˜7.21(m,2H), 7.29˜7.37(m,6H)

[0251] Reference 4-a

[0252] Synthesis of Compound (8-2)

[0253] D-p-Benzyloxyphenylglycine

[0254] To a solution of D-p-hydroxyphenylglycine (16.7 g) in 2 N sodiumhydroxide (50 mL) was added a solution of copper sulfate (12.5 g) inwater (100 mL). The mixture was stirred at 60° C. for 1 hr. Aftercooling to room temperature, 2 N sodium hydroxide (50 mL), methanol (50mL) benzyl bromide (13.0 mL) were added. The mixture was stirred at roomtemperature for 20 hr. Resulting salts were collected by suction, washedwith water and acetone and the residue dissolved in 1 N hydrochloricacid (300 mL) and the mixture was stirred at room temperature for 1 hr.Resulting salts were collected by suction, washed with water and acetoneand dried to give 13.18 g (51.3%) of the compound (8-2).

[0255] Mass m/z: 212 (M-45)⁺, 122, 91(base), 65

[0256] IR (KBr): 3022, 1587, 1509, 1389, 1248, 1008 cm⁻¹

[0257]¹H-NMR (CD₃OD): 5.07(s,1H), 5.16(s,2H), 7.12(d,J=6.8 Hz,2H),7.34˜7.48(m,5H), 7.45(d, J=6.8 Hz,2H)

[0258] Reference 4-b

[0259] Synthesis of Compound (8-3)

[0260] D-p-Benzyloxyphenyl-N-(tert-buthoxycarbonyl)glycine

[0261] To a solution of the compound (8-2) (12.53 g) intetrahydrofuran-water (140 mL) were added triethylamine (16.4 mL) anddi-tert-butyl-dicarbonate (13.5 mL) at 0 t. After the mixture wasstirred at room temperature for 4 hr, the mixture was concentrated underreduced pressure. The residue was added with 10% citric acid solution topH 4 and extracted with ethyl acetate (100 mL×3). The organic layer waswashed with water (100 mL×3), brine (100 mL) and dried (Na₂SO₄). Afterremoval of the organic solvent under reduced pressure, 17.4 g(quantitative) of the compound (8-3) was obtained.

[0262] Mass m/z: 357 (M+), 331, 301, 283, 256, 212, 148, 120, 91 (base)

[0263] IR (KBr): 3298, 2968, 1791, 1656, 1608, 1506, 1452, 1392, 1242,1161 cm⁻¹

[0264]¹H-NMR (CDCl₃): 1.23(s,9H), 5.05(bs,3H), 6.94(d,J=8.3 Hz,2H),7.32˜7.41(m,8H)

[0265] Reference 4-c

[0266] Synthesis of Compound (84)

[0267] Benzyl(3S)-3-[4-(benzyloxy)phenyl]-3-[(tert-butoxy)carbonylamino]propionate

[0268] To a solution of the compound (8-3) (14.4 g) in tetrahydrofuran(80 mL) were added triethylamine (5.9 mL) and isobutylchloroformate (5.8mL) at 0° C. After the mixture was stirred for 40 min, ether solution ofdiazomethane, prepared from N,N-dimethylnitrosourea (30.0 g) and 40%potassium hydroxide solution (100 mL), was added. The mixture wasstirred for 1.5 hr and then quenched with acetic acid. Ether (100 mL)and water (100 mL) were added to the mixture. The separated organiclayer was washed with satd.Na₂CO₃ solution (100 mL×2), brine (100 mL),dried (Na₂SO₄) and evapolated. To a solution of the residue intetrahydrofuran (80 mL)-water (15 mL) was added a solution of silverbenzoate (0.93 g) in triethylamine (8.3 mL). After the mixture wasstirred at room temperature for 2 hr, the mixture was diluted with ether(100 mL). The ether solution was washed with 10% hydrochloric acid (50mL×2), water (100 mL×4), brine (50 mL), dried (Na₂SO₄) and concentrated.To a solution of the residue in acetonitrile (80 mL) were added DBU (7.0mL) and benzylbromide (5.7 mL). The mixture was stirred at roomtemperature for 4 hr and diluted with ethyl acetate. The ethyl acetateextract was washed successively with 10% citric acid solution (50 mL×2),satd.Na₂CO₃ (100 mL), brine (100 mL), dried (Na₂SO₄) and evaporated. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane=1/2) to give 10.35 g (55.7%) of the compound (8-4).

[0269] Mass m/z 461 (M⁺), 404, 360, 314, 270, 212, 180, 121, 91, 57(base)

[0270] IR (KBr) 3394, 2956, 1731, 1689, 1500, 1290, 1224, 1149 cm⁻¹

[0271]¹H-NMR(CDCl₃): 1.51(s,9H), 2.89˜3.12(m,2H), 5.10(s,4H),5.09˜5.13(m,1H), 6.99(d, J=8.8 Hz,2H), 7.30˜7.54(m,12H)

[0272] Reference 4-d

[0273] Synthesis of Compound (8-5)

[0274] Benzyl (3S)-3-amino-[4-(benzyloxy)phenyl]propionate Hydrochloride

[0275] To a solution of the compound (8-4) (3.00 g) in ethyl acetate (30mL) was added 17% hydrochloric acid in ethanol (10 mL). The mixture wasstirred for 3 hr and concentrated under reduced pressure. To the residuewas added ethyl acetate-hexane (1/4) in order to crystallize. Theresulting crystals were filtered and dried to give 2.46 g (95.2%) of thecompound (8-5).

[0276] Mass m/z: 361 (M-36.5)⁺, 344, 270, 147, 121, 91 (base), 65

[0277] IR (KBr): 3016, 2908, 1725, 1581, 1512, 1299, 1245, 1185 cm⁻¹

[0278]¹H-NMR(CDCl₃): 3.05(d,J=6.4 Hz,18.3 Hz,1H), 3.27(d,J=6.4 Hz,16.8Hz,1H), 4.64˜4.65(m, 1H), 4.94˜5.03(m,4H), 6.89(d,J=8.7 Hz,2H),7.15˜7.41(m,12H), 8.77˜8.78(m,3H)

[0279] Reference 4-e

[0280] Synthesis of Compound (8-6)

[0281] (4S)-4-[4-(benzyloxy)phenyl]azetidine-2-one

[0282] To a suspension of the compound (8-5) (6.48 g) in ethyl acetatewere added water (15 mL) and 1 M potassium carbonate solution to makealkaline. The mixture was extracted with ethyl acetate (30 mL×2). Theorganic layer was washed with brine (50 mL), dried (Na₂SO₄) andevaporated. To a solution of the residue in benzene (60 mL) were addedtriethylamine (3.6 mL) and chlorotrimethylsilane (2.7 mL). The mixturewas stirred at room temperature for 14 hr and filtered through a pad ofCelite. The filtrate was evaporated under reduced pressure and theresidue was dissolved in ether (65 mL) and a solution of 2 Mtert-butylmagnessium chloride in ether (10.7 mL) was added at 0° C. andstirred at room temperature for 18 hr and then saturated ammoniumchloride solution (50 mL), ethyl acetate (50 mL) and 10% hydrochloricacid (50 mL) were added successively at 0° C. After the resultingmixture was stirred at room temperature for 1 hr, the water layer wasextracted with ethyl acetate. The combined ethyl acetate extracts waswashed with water (50 mL), satd. NaHCO₃ (50 mL), and brine (50 mL),dried (Na₂SO₄) and evaporated. The residue was purified by silica gelcolumn chromatography (chloroform/acetone=10/1) to give the objectivecompound as a crude solid. This solid was purified by washing with ethylacetate-hexane to give 2.50 g (60.7%) of the compound (8-6).

[0283] Mass m/z: 253 (M⁺), 162, 91(base), 65

[0284] IR (KBr): 3184, 1749, 1698, 1540, 1410, 1248, 1100 cm⁻¹

[0285]¹H-NMR(CDCl₃): 2.84˜2.88(d,J=1.0 Hz,2.4 Hz,15.1 Hz,1H),3.39˜3.44(d,J=2.4 Hz, 5.4 Hz, 14.8 Hz,1H), 4.68(d,J=4.9 Hz,14.9 Hz,1H),5.08(s,2H), 6.09(bs,1H), 6.97(d,J=2.9 Hz,7.8 Hz,2H), 7.28˜7.44(m,7H)

[0286] Reference 4-f

[0287] Synthesis of(4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)azetidine-2-one

[0288] To a solution of the compound (8-6) (1.00 g) in dichloromethane(10 mL) were added triethylamine (0.8 mL), 4-fluorophenylboronic acid(1.11 g) and copper aceate (0.75 g). The mixture was refluxed for 48 hrand evaporated under reduced pressure. The residue was partitioned inethyl acetate (50 mL) and water (50 mL). The water layer was extractedwith ethyl acetate (50 mL×3). The combined ethyl acetate extracts werewashed successively with water (50 mL), 10% hydrochloric acid (50 mL),saturated sodium bicarbonate solution (50 mL), and brine (50 mL), driedover anhydrous sodium sulfate and concentrated. The residue was purifiedby silica gel column chromatography (benzene/ether=12/1) to give asolid, which was recrystallized from ethyl acetate-hexane to give 1.06 g(77.3%) of the objective compound (8-26).

[0289] Mass m/z: 347 (M⁺), 256, 210, 137, 91 (base), 65

[0290] IR (KBr): 1731, 1620, 1506, 1380, 1242 cm⁻¹

[0291]¹H-NMR(CDCl₃): 2.93(d,J=3.0 Hz,15.2 Hz,1H), 3.52(d,J=5.4 Hz, 15.2Hz,1H), 4.93(d,J=2.4 Hz, 5.4 Hz,1H), 5.05(s,2H), 6.90˜6.99(m,4H),7.24˜7.43(m,9H)

[0292] Reference 4-g

[0293] Synthesis of Compound (8-27)

[0294] (4S)-1-(4-fluorophenyl)-4-(hydroxyphenyl)azetidine-2-one

[0295] A solution of the compound 8-26 (2.00 g) obtained above stepreference 4-f in ethyl acetate-methanol (50 mL) was hydrogenated at roomtemperature for 9 hr in the presence of 5% palladium on carbon (0.20 g).After removal of the catalyst through a pad of Celite, the solvent wasevaporated and the residue was purified by silica gel columnchromatography (chloroform/acetone=10/1) to give 1.36 g (91.9%) of thecompound (8-27).

[0296] Mass m/z: 257 (M⁺), 214, 120(base), 91, 58

[0297] IR (KBr): 3106, 1707, 1620, 1503, 1453, 1383, 1257, 1218 cm⁻¹

[0298]¹H-NMR(CDCl₃):2.93(d,J=2.4 Hz,15.7 Hz, 1H), 3.53(d,J=5.9 Hz,15.2Hz, 1H), 4.94(d,J=2.9 Hz, 5.4 Hz,1H), 5.22(s,1H), 6.85(d,J=8.3 Hz,2H),6.93(s,J=8.8 Hz,2H), 7.23˜7.27(m,4H)

[0299] Reference 4-h

[0300] Synthesis of4-[(2S)-1-(4-fluorophenyl)-4-oxoazetidine-2-yl]phenyltrifluoromethanesulfonate

[0301] To a suspension of the compound (8-27) (0.35 g) indichloromethane (10 mL) were added pyridine (0.12 mL) andtrifluoromethanesulfonic anhydride (0.26 mL) at 0° C. The mixture wasstirred for 1 hr and poured into ice-cold water (20 mL). The resultingmixture was extracted with ethyl acetate (30 mL×2). The combined ethylacetate extracts were washed with 10% hydrochloric acid (20 mL),saturated sodium bicarbonate solution (40 mL), brine (30 mL), dried overanhydrous sodium sulfate and evaporated. The residue was purified bysilica gel column chromatography (ethyl acetate/hexane=1/3) to give 0.48g (90.7%) of the objective compound (8-28).

[0302] Mass m/z: 389 (M⁺), 347, 252, 214, 186, 137, 119(base), 69

[0303] IR (KBr): 1734, 1509, 1416, 1383, 1248, 1212, 1131, 900 cm⁻¹

[0304]¹H-NMR(CDCl₃): 2.94(d,J=2.5 Hz,15.2 Hz, 1H), 3.16(d,J=5.9 Hz,15.2Hz, 1H), 5.04(d,J=2.5 Hz, 5.4 Hz,1H), 6.98(t,J=8.8 Hz,2H),7.21˜7.25(m,2H), 7.31(d,J=2.0 Hz,6.8 Hz,2H), 7.45(d, J=2.2 Hz,6.8 Hz,2H)

[0305] Reference 4-i

[0306] Synthesis of Compound (8-29)

[0307](4S)-4-[4-{(2S,5S,3R,4R,6R)-6-[(benzyloxy)methyl]-3,4,5-tribenzyloxy}perhydro-2H-pyran-2-yl]methyl)phenyl]-1-(4-fluorophenyl)azetidine-2-one

[0308] To a solution of the compound (8-28) (0.32 g) in tetrahydrofuran(4.1 mL) was added 0.5 M 9-BBN in tetrahydrofuran (3 mL) and the mixturewas refluxed for 6 hr. After cooling to room temperature, 3 M potassiumphosphate solution (0.6 mL), tetrahydrofuran (4.7 mL), the compoundobtained in reference 4-h (0.22 g) and PdCl₂(dppf) (0.042 g) were addedto the mixture and the resulting mixture was stirred at 50° C. for 16hr. To the mixture were added water (30 mL) and ethyl acetate (30 mL)and the resulting mixture was filtered through a pad of Celite. Thefiltrate was extracted with ethyl acetate (30 mL×2). The combined ethylacetate extracts were washed with water (30 mL×2) and brine (30 mL),dried over anhydrous sodium sulfate and evaporated. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane=1/4)to give 0.209 g (45.4%) of the compound (8-29).

[0309] Mass (ESI) m/z: 800 (M+Na(23))⁺

[0310] IR (KBr): 2896, 1746, 1509, 1377, 1095, 1068, 750 cm⁻¹

[0311]¹H-NMR(CDCl₃): 2.69˜2.75(d,J=7.8 Hz,14.7 Hz,1H), 2.89(d,J=2.5Hz,15.1 Hz,1H), 3.12(d, J=1.5 Hz,14.2 Hz,1H), 3.30˜3.37(m,2H),3.46˜3.53(m,2H), 3.59˜3.74(m,8H), 4.45˜4.64(m,4H), 4.81˜4.94(m,5H),6.90(t,J=8.8 Hz,2H), 7.19˜7.35(m,26H)

[0312] Reference 4-j

[0313] Synthesis of Compound (8-30)

[0314] Methyl3-{(4S,3R)-4-[4-{(2S,5S,3R,4R,6R)-6-(benzyloxymethyl)-3,4,5-tribenzyloxy}perhydro-2H-pyran-2-yl]methyl}phenyl]-1-(4-fluorophenyl)oxoazetidine-3-yl}propionate

[0315] To a solution of 2 M lithium diisopropylamide (1.3 mL) intetrahydrofuran (3 mL) was added a solution of the compound (8-29) (1.00g) in tetrahydrofuran (1.5 mL) at −78° C. and the mixture was stirredfor 1 hr and a solution of methyl acrylate (0.132 g) in tetrahydrofuran(2 mL) was added to the mixture. The resulting mixture was stirred for0.5 hr and the mixture was quenched with saturated ammonium chloridesolution (30 mL) and extracted with ethyl acetate (60 mL×2). Thecombined ethyl acetate extracts were washed with water (50 mL), driedover anhydrous sodium sulfate and evaporated. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane=1/4) to give0.793 g (71.8%) of the compound (8-30).

[0316] Mass (ESI) m/z: 864 (M+1)⁺

[0317] IR (KBr): 2854, 1740, 1509, 1452, 1362, 1215, 1140, 1098 cm⁻¹

[0318]¹H-NMR (CDCl₃): 2.19˜2.23(m,2H), 2.47˜2.59(m,2H), 2.72(d,J=8.8 Hz,14.6 Hz,1H), 3.04˜3.13(m,2H), 3.30˜3.37(m,2H), 3.42˜3.48(m,1H),3.64(s,3H), 3.61˜3.74(m,4H), 4.47˜4.63(m,5H), 4.81˜4.94(m,4H),6.90(t,J=8.8 Hz,2H), 7.15˜7.35(m,26H)

[0319] Reference 4-k

[0320] Synthesis of Compound (8-31)

[0321] (4S,3R)-4-[4-({(2S,5S,3R,4R,6R)-6-(benzyloxy)methyl}-3,4,5-tribenzyloxy)perhydro-2H-pyran-2-yl]methyl)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidine-2-on

[0322] To a solution of the compound (8-30) (1.75 g) intetrahydrofuran-methanol (20 mL) were added water (5 mL) and lithiumhydroxide (0.084 g). The mixture was stirred at room temperature for 4hr. The reaction mixture was acidified by addition of 10% hydrochloricacid and extracted with ethyl acetate (30 mL×3). The combined ethylacetate extracts were concentrated under reduced pressure, and theresidue was passed through a short silica gel column (ethylacetate/hexane=1/1) to give the crude product which was subjected to thenext reaction without further purification. To a solution of thecompound obtained above in dichloromethane (8.4 mL) was added 2 M oxalylchloride (0.84 mL) in dichloromethane and the mixture was stirred atroom temperature for 16 hr. Removal of the organic solvent gave thecrude acid chloride. To a suspension of zinc chloride (0.368 g) intetrahydrofuran (8 mL) was added 4-fluorophenylmagnesium bromide,prepared from magnesium (0.084 g) and 4-bromofluorobenzene (0.47 g) intetrahydrofuran (8 mL). The mixture was stirred at room temperature for1 hr and tetrakis(triphenylphosphine)palladium (0.068 g) was added at10° C. After the mixture was stirred for 5 min, the acid chlorideobtained above in tetrahydrofuran (7 mL) was added. The resultingmixture was stirred at room temperature for 1 hr, and then quenched with10% hydrochloric acid (20 mL). The mixture was extracted with ethylacetate (50 mL×2). The organic layer was washed with water (50 mL X 2)and brine (50 mL), dried over anhydrous sodium sulfate and evaporated.The residue was purified by silica gel column chromatography (ethylacetate/hexane=1/5) to give 0.910 g (73.7%) of the compound (8-31).

[0323] Mass (ESI) m/z: 551 (M+Na(23)+1)⁺

[0324] IR (KBr): 2920, 1746, 1690, 1610, 1310, 1280, 1240, 1100 cm⁻¹

[0325]¹H-NMR(CDCl₃):2.23˜2.42(m,2H), 2.72(d,J=8.8 Hz,14.7 Hz,1H),3.09˜3.74(m,11H), 4.46˜4.63(m,4H), 4.66(d,J=2.5 Hz,1H), 4.81˜4.94(m,4H),6.91(t,J=8.8 Hz,2H), 7.11(t,J=8.3 Hz, 2H), 7.33˜7.89(m,26H),7.96˜8.00(m,2H)

Example 5

[0326] Synthesis of Compound (26)

[0327](4S,3R)-4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidine-2-one

[0328] To a solution of the compound (8-31) (0.27 g) in dichloromethane(5.4 mL) was added 1 M borontribromide in dichloromethane (1.8 mL) at−78° C. and the mixture was stirred for 1 hr. The mixture was pouredinto ice-water (30 mL) and extracted with chloroform (30 mL×3). Thecombined chloroform extracts were washed successively with water (50mL), saturated sodium bicarbonate solution (50 mL), and brine (50 mL),dried over anhydrous sodium sulfate and concentrated. The residue waspurified by silica gel column chromatography (chloroform/methanol=8/1)to give 0.147 g (89.1%) of the compound (26).

[0329] Mass (ESI) m/z: 568 (M+1)⁺

[0330] IR (KBr): 3400, 2902, 1737, 1680, 1596, 1506, 1386, 1224, 1152,1134, 1086 cm⁻¹

[0331]¹H-NMR (CD₃OD):2.28˜2.34(m,2H), 2.74(d,J=8.3 Hz, 14.6 Hz,1H),3.09˜3.39(m,10H), 3.64(d,J=5.3 Hz, 11.7 Hz,1H), 3.78(d,J=2.4 Hz, 11.7Hz,1H), 4.95(d,J=2.4 Hz,1H), 7.01˜7.05(m,2H), 7.22˜7.26(m,2H),7.27˜7.38(m,6H), 8.06˜8.10(m,2H)

Example 6

[0332] Synthesis of Compound (22)

[0333]3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-(4S,3R)-4(4-[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl)phenyl)-1-(4-fluorophenyl)azetidine-2-one

[0334] To a solution of the compound (8-32) (0.061 g) in dichloromethane(0.6 mL) was added the compound (26) (0.115 g) in dichloromethane (2.8mL) at −20° C. and the mixture was stirred for 2 hr. The mixture wasquenched by addition of methanol (2 mL) and stirred for 1 hr. Ethylacetate (30 mL) and 10% hydrochloric acid (30 mL) were added and theresulting mixture was extracted with ethyl acetate (30 mL×3). Theorganic layer was washed with water (30 mL X 3) and brine (50 mL), driedover anhydrous sodium sulfate and evaporated. The residue was purifiedby silica gel column chromatography (chloroform/methanol=10/1) to give0.089 g (77.1%) of the compound (22).

[0335] Mass (ESI) m/z: 570 (M+1)⁺

[0336] IR (KBr):3370, 2902, 1725, 1506, 1389, 1218, 1083, 1011 cm⁻¹

[0337]¹H-NMR (CD₃OD): 1.88˜1.99(m,4H), 2.76(d,J=8.3 Hz, 14.2 Hz,1H),3.09˜3.40(m,7H), 3.64(d,J=5.4 Hz, 11.5 Hz,1H), 3.79(d,J=2.0 Hz, 11.7Hz,1H), 4.65(dt,J=4.8 Hz, 6.4 Hz,1H), 4.85(d,J=2.0 Hz,1H),7.00˜7.09(m,4H), 7.29˜7.40(m,8H)

Example 7

[0338] Synthesis of Compound (8-33)

[0339](4S,3R)-4-[4-{(2S,5S,3R,4R,6R)-6-[(Benzyloxy)methyl]-3,4,5-tribenzyloxy}perhydro-2H-pyran-2-yl]methyl)phenyl)-1-(4-fluorophenyl)-3-[(2E)-3-(4-fluorophenyl)-2-propenyl]azetidine-2-one

[0340] To a solution of the compound (8-29) in tetrahydrofuran (3 mL)was added 2 M lithium diisopropylamide (0.6 mL) in tetrahydrofuran at−78° C. and the mixture was stirred for 30 min. 1.8 mL of DMPU(1,3-dimethyl-3,4-5,6-tetrahydro-2(1H)-pyrimidinone) was added to themixture and the mixture was stirred for 30 min. To the reaction mixturewas added 4-fluorocinnamylbromide (0.111 g) in tetrahydrofuran (1.5 mL)and the resulting mixture was stirred for 30 min. The reaction mixturewas quenched with a solution of saturated ammonium chloride solution (30mL) and extracted with ethyl acetate (50 mL×2). The organic layer waswashed successively with water (50 mL×3), brine (50 mL), dried overanhydrous sodium sulfate and evaporated. The residue was purified bysilica gel column chromatography (ethyl acetate/hexane=1/5) to give0.253 g (64.4%) of the compound (8-33).

[0341] Mass (ESI) m/z: 934 (M+Na(23))⁺

[0342] IR (KBr): 2890, 1746, 1509, 1383, 1359, 1224, 1137, 1098 cm⁻¹

[0343]¹H-NMR (CDCl₃): 2.63˜2.88(m,3H), 3.12(d,J=1.9 Hz, 14.7 Hz,1H),3.20˜3.38(m,4H), 3.47˜3.48(m,1H), 3.59˜3.74(m,5H), 4.45˜4.63(m,4H),4.65(d,J=2.4 Hz,1H), 4.81˜4.94(m,4H), 6.12(dt,J=6.8 Hz, 14.6 Hz, 1H),6.45(d,J=14.7 Hz, 1H), 6.90(t,J=8.8 Hz,2H), 6.95(t,J=8.7 Hz,2H),7.14˜7.35(m,28H)

Example 8

[0344] Synthesis of Compound (25)

[0345]4-(4-[(5S,2R,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methyl}phenyl)-(4S,3R)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)propyl]-azetidine-2-on

[0346] A solution of the compound (8-33) (0.23 g) inmethanol-tetrahydrofuran (10 mL) was hydrogenated at room temperaturefor 5 hr in the presence of 5% palladium on carbon (0.115 g). Afterremoval of the catalyst through a pad of Celite, the solvent wasevaporated. The residue was purified by silica gel column chromatography(chloroform/methanol=9/1) to give 0.113 g (81.1%) of the compound (25).

[0347] Mass (ESI) m/z: 554 (M+1)⁺

[0348] IR (KBr) 3394, 2908, 1737, 1506, 1386, 1218, 1089 cm⁻¹

[0349]¹H-NMR (CD₃OD):1.88˜1.95(m,4H), 2.66(t,J=7.3 Hz,2H), 2.75(d,J=8.3Hz, 14.2 Hz,1H), 3.09˜3.40(m,7H), 3.64(d,J=5.8 Hz, 11.7 Hz,1H),3.78(d,J=2.5 Hz, 11.7 Hz,1H), 4.91 (d,J=2.0 Hz, 1H), 6.97˜7.04(m,4H),7.18˜7.33(m,6H), 7.38(d,J=8.3 Hz,2H)

[0350] Synthesis of Compound (11-3)

[0351] Methyl5-(4-aza-10,10-dimethyl-3-dioxo-3-thiatricyclo[5,2,1,1,5]decane-4-yl)-5-oxopentanoate

[0352] To a solution of (R)-(+)-2,10-camphorsultam (0.89 g) in toluene(14 mL) was added sodium hydride (0.182 g) at 0° C., and the mixture wasstirred at room temperature for 20 min. To the reaction mixture wasadded methyl 5-chloro-5-oxo-valerate (0.816 g) and the resulting mixturewas stirred at room temperature for 1 hr. The reaction mixture wasquenched by addition of saturated ammonium chloride (40 mL) andextracted with ethyl acetate (50 mL×2). The organic layer was dried overanhydrous sodium sulfate and evaporated. The residue was purified bysilica gel column chromatography (chloroform/acetone=40/1, then ethylacetate/hexane=1/2) to give 1.30 g (91.8%) of the compound (11-3).

[0353] Mass m/z: 343 (M⁺), 312, 279, 129(base), 101

[0354] IR (KBr): 2944, 1720, 1689, 1440, 1413, 1389, 1335, 1215, 1050cm⁻¹

[0355]¹H-NMR (CD₃OD): 0.97(s,3H), 1.16(s,3H), 1.35˜1.41(m,2H),1.87˜2.12(m,7H), 2.39(t, J=8.3 Hz,2H), 2.78(t,J=7.4 Hz,2H), 3.46(q,J=4.4Hz,2H), 3.67(m,3H), 3.85˜3.88(m,1H)

[0356] Reference 5-b

[0357] Synthesis of compound (11-10)

[0358] Methyl(4R)-4-{(1S)-(4-bromophenyl[(4-fluorophenyl)amino]methyl)-5-(4-aza-10,10-dimethyl-,3-dioxo-3-thiatricyclo[5,2,1,1,5]decane-4-yl)-5-oxo-pentanoate

[0359] To a solution of titanium tetrachloride (0.23 mL) indichloromethane (10 mL) was added titanium tetraisopropoxide (0.2 mL) at0° C. and the mixture was stirred for 5 min. The compound (11-3) (0.65g) in dichloromethane (3.5 mL) was added to the mixture and stirred for5 min. Diisopropylethylamine (0.72 mL) was added to the mixture andstirred for 1 hr and then cooled to −20° C.(1Z)-1-aza-2-(4-bromophenyl)-1-(4-fluorophenyl)ethene (1.15 g) indichloromethane (3.5 mL) was added at −20° C. and the resulting mixturewas stirred for 3 hr. The reaction mixture was quenched by successiveaddition of acetic acid (1 mL) in dichloromethane (5 mL) and 10%hydrochloric acid (30 mL), and extracted with ethyl acetate (50 mL×2).The organic layer was washed successively with water (50 mL), saturatedsodium bicarbonate solution (50 mL), brine (50 mL), dried over anhydroussodium sulfate and evaporated. The residue was purified by silica gelcolumn chromatography (chloroform/acetone=50/11 then ethylacetate/hexane=1/2) to give 0.708 g (61.1%) of the compound (11-10).

[0360] Mass m/z: 622 (M+2)⁺, 620 (M+), 343, 278, 200, 135, 95

[0361] IR (KBr): 3376, 2944, 1734, 1683, 1509, 1437, 1269, 1131, 1059,1008 cm⁻¹

[0362]¹H-NMR(CDCl₃): 0.95(s,3H), 0.95(s,3H), 1.24˜1.39(m,2H),1.60˜2.04(m,5H), 2.28˜2.33(m,2H), 3.45˜3.57(m,3H), 3.62(s,3H),3.79˜3.91(m,1H), 4.56(t,J=9.3 Hz,1H), 4.95(d, J=10.2 Hz,1H),6.34˜6.38(m,2H), 6.71˜6.76(m,2H), 7.17(d,J=8.3 Hz,2H), 7.41 (d,J=8.3 Hz,2H)

[0363] Reference 5-c

[0364] Synthesis of compound (11-11)

[0365] Methyl3-{(4S,3R)-4-(4-bromophenyl)-1-(4-fluorophenyl)-2-oxoazetidine-3-yl}propionate

[0366] To a solution of the compound (11-10) (0.52 g) in toluene (10 mL)was added BSA (N,O-bistrimethylsilylacetamide, 0.41 g) at 50° C. and themixture was stirred for 30 min. 1 M Tetrabutylammonium fluoride (0.84mL) in tetrahydrofuran was added and the resulting mixture was stirredat 50° C. for 3 hr. After cooled to room temperature, the mixture wasquenched with methanol (1 mL). The mixture was stirred for 5 min andthen 10% hydrochloric acid (15 mL) was added. The mixture was extractedwith ethyl acetate (50 mL×2). The organic layer was washed successivelywith water (50 mL), saturated sodium bicarbonate solution (50 mL), andbrine (50 mL), dried over anhydrous sodium sulfate and evaporated. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane=1/3) to give 0.227 g (66.7%) of the compound (11-11).

[0367] Mass m/z: 407 (M+2)⁺, 405 (M⁺), 270, 208, 169, 129(base), 95

[0368] IR (KBr): 2938, 1758, 1503, 1440, 1371, 1233, 1101 cm⁻¹

[0369]¹H-NMR(CDCl₃): 2.21˜2.56(m,2H), 2.49˜2.61(m,2H), 3.08˜3.12(m,1H),3.67(s,3H), 4.66(d,J=2.5 Hz,1H), 6.92˜6.97(m,2H), 7.18˜7.22(m,4H), 7.51(d,J=1.9 Hz,6.3 Hz,2H)

[0370] Reference 6

[0371] Synthesis of Compound (12-4)

[0372] Methyl3-{(4S,3R)-4-[4-(3-{(2S,5S,3R,4R,6R)-6-(benzyloxymethyl)-3,4,5-(tribenzyloxy)perhydro-2H-pyran-2-yl}-1-propen)phenyl]-1-(4-fluorophenyl)oxoazetidine-3-yl}propionate

[0373] To a solution of the compound (11-11) (575 mg) and3-(2,3,4,6-tetra-o-benzyl-β-D-glucopyranosyl)-1-propene (1.2 g) intriethylamine (5 mL) were added tri-o-tolylphosphine (43 mg) andpalladium acetate (16 mg). The mixture was stirred at 100° C. for 13 hr.The mixture was cooled to room temperature and diluted with ethylacetate (50 mL) and the ethyl acetate layer was washed with 10%hydrochloric acid, brine, dried over anhydrous sodium sulfate andevaporated. The residue was purified by silica gel column chromatography(ethyl acetate/hexane=1/4) to give 1.1 g (87.0%) of the compound (12-4).

[0374] This compound can be used as an intermediate for the synthesis ofthe compound depicted in general formula (I) in reference 4-l, 4-j, and4-k, and example 5, 6, 7, and 8.

[0375] Mass (ESI) m/z: 890 (M+1)⁺

[0376] IR (neat): 3016, 2896, 1741, 1503, 1371, 1215, 1092, 831, 747cm⁻¹

[0377]¹H-NMR(CDCl₃): 2.23(q,J=7.8 Hz,2H), 2.44-2.60(m,4H), 3.11 (m,1H),3.33-3.44(m,3H), 3.58-3.75(m,4H), 3.66(s,3H), 4.54-4.94(m,9H),6.38(m,2H), 6.91-7.32(m,28H)

[0378] Reference 7

[0379] Synthesis of Compound 50

[0380](4S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{[(2S,5S,3R,4R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)perhydro-2H-pyran-2-yl]methoxypropyl-3-yl}phenyl-1-(4-fluorophenyl)azetidine-2-one

[0381] To a suspension of sodium hydride (4.5 mg) in DMF(N,N-dimethylformamide, 1 mL) was added2,3,4,6-o-tetrabenzyl-1-deoxy-β-D-glucopyranosyl methanol (62 mg) in DMF(3 mL) at 0° C., and the mixture was stirred for 20 min.(4S,3R)-4-[4-(3-bromopropyl)phenyl]-3-[(3S)-(4-fluorophenyl)-3-hydroxypropyl]-2-azetidine-2-one(57 mg) in DMF (3 mL) and the resulting mixture was stirred at roomtemperature for 2 hr. The reaction mixture was poured into ice-coldwater (20 mL) and extracted with ethyl acetate (30 mL X 2). The organiclayer was washed with water (30 mL×2) and brine (40 mL), dried overanhydrous sodium sulfate and evaporated. A solution of the residue intetrahydrofuran-methanol (1/1) (10 mL) was hydrogenated at roomtemperature for 9 hr in the presence of 5% palladium on carbon (50 mg).After removal of the catalyst, the solvent was evaporated. The residuewas purified by silica gel column chromatography(chloroform/methanol=10/1) to give 43 mg (61.2%) of the compound 50.

[0382] Mass (ESI) m/z: 628 (M+1)⁺

[0383] IR (neat): 3388, 2902, 1734, 1509, 1389, 1218, 1080 cm⁻¹

[0384]¹H-NMR (CD₃OD): 1.87-1.97(m,6H), 2.73(t,J=7.4 Hz,2H),3.10-3.5(m,1H), 3.12-3.39(m,5H), 3.52-3.57(m,2H), 3.53-3.69(m,2H),3.78(d,J=2.0 Hz,10.7 Hz, 1H), 3.87(d,J=1.0 Hz, 10.5 Hz, 1H),4.64(bt,1H), 4.85(d,J=2.5 Hz,1H), 7.00-7.09(m,4H), 7.27-7.37(m,6H)

Example 9

[0385] Synthesis of Compound 19-9

[0386](4S)-4-(4-{[(2S,5S,3R,4R,6R)-6-(benzyloxy)methyl-3,4,5-tribenzyloxy]perhydro-2H-pyran-2-yl}ethyl-phenyl)-1-phenyl-azetidine-2-one

[0387] Reference 8-a

[0388] Synthesis of Compound (19-6)

[0389] (3R)-3-(4-Bromophenyl)-3-hydroxy-N-phenylpropanamide

[0390] To a solution of 3-(4-bromophenyl)-3-oxo-N-phenylpropaneamide(950 mg) in ethanol-dichloromethane (3:1, 4 mL) was addedRuCl₂[(S)-BINAP](dichloro[(S)-(−)-2,2′-bis-(diphenylphosphino)-1,1′-binaphthyl]ruthenium(II))cataltst (12 mg). The mixture was catalytic asymmetric hydrogenated at100° C. for 6 hr under 5 atom H₂ atmosphere. After cooling to roomtemperature, the mixture was concentrated. The resulting crystals werecorrected and dried to give 725 mg (yield 76%, asymmetric yield 99%e.e.) of the compound (19-6).

[0391] m.p.=210-212° C.

[0392] [α]^(D): +33.0 (c=1.0, THF)

[0393] Mass m/z: 319 (M⁺),183, 157, 135, 93 (base), 65

[0394] IR (KBr): 3316, 1614, 1599, 1530, 1443, 1368, 1065, 693 cm⁻¹

[0395]¹H-NMR (DMSO): 2.69(dd,J=4.4 Hz,14.2 Hz,1H), 2.77(dd,J=8.8 Hz,14.2Hz,1H), 5.16(n,1H), 5.69(d,J=4.4 Hz,1H), 7.14(t,J=7.3 Hz,1H),7.40(d,J=7.8 Hz,2H), 7.46(d, J=8.3 Hz,2H), 7.64(d,J=8.3 Hz,2H),7.69(d,J=7.8 Hz,2H)

[0396] Reference 8-b

[0397] Synthesis of compound (19-7)

[0398] (4S)-4-(4-Bromophenyl)-1-phenyl-azetidine-2-one

[0399] To a solution of the compound (19-6) (500 mg) in tetrahydrofuran(7 mL) were added DIAD (diisopropylazodicarboxylate) (0.67 mL) and PPh₃(479 mg) at −78°. The mixture was slowly warmed to room temperature andstirred for 4 hr. The mixture was concentrated, and the residue waspurified by silica gel column chromatography (ethyl acetate/hexane=1/5to 1/2) to give 260 mg (55.2%) of the compound 19-7.

[0400] m.p.=113-115° C.

[0401] [α]^(D): −146.0 (c=1.0, CHCl₃)

[0402] Mass m/z: 301 (M⁺), 260, 184, 103, 77 (base)

[0403] IR (KBr): 1728, 1599, 1485, 1377, 1149, 828, 750 cm⁻¹

[0404]¹H-NMR (CDCl₃): 2.91 (dd,J=2.9 Hz, 15.1 Hz,1H), 3.56(dd,J=5.4 Hz,15.1 Hz,1H), 4.98(dd,J=2.4 Hz,5.9 Hz,1H),7.04-7.52(m,9H)

[0405] Synthesis of Compound (19-9)

[0406] To a solution of Zn(Cu) (106 mg) in tetrahydrofuran-HMPA (3:1, 4mL) was added the compound (19-8) (1.0 g), and the mixture was refluxedfor 3 hr. Palladium acetate (1.7 mg) and2-(di-tert-butylphosphino)biphenyl (4.4 mg) were added to the mixture at0° C. After 5 min, the compound (19-7) (223 mg) was added, and themixture was warmed to room temperature. 10% aqueous HCl (50 mL) andethyl acetate (30 mL) were added to the mixture, and filtered. Thefiltrate was extracted with ethyl acetate (50 mL×2). The organic layerwas washed with water (50 mL) and brine (50 mL), dried over anhydroussodium sulfate and evaporated. The residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane=1/4) to give 480 mg (84.3%)of the compound (19-9).

[0407] m.p.=95-97° C.

[0408] [α]^(D): −61.2 (c=1.0, CHCl₃)

[0409] ESI-MS (m/z): 796 (M+Na)⁺, 774(M+1)⁺

[0410] IR (KBr): 2854, 1749, 1599, 1497, 1452, 1371, 1212, 1068 cm⁻¹

[0411]¹H-NMR (CDCl₃): 1.71-1.75(m, 1H), 2.04-2.10(m,1H),2.63-2.74(m,1H), 2.81-2.87(m,1H), 2.94(dd,J=2.4 Hz,15.1 Hz,1H),3.18-3.22(m,1H), 3.29(t,J=13.1 Hz,1H), 3.36-3.40(m,1H), 3.53(dd,J=5.9Hz, 5.1 Hz,1H), 3.59-3.75(m,4H), 4.55-4.66(m,4H), 4.80-4.88(m,4H),4.96-4.98(m,1H), 7.02(t,J=6.8 Hz,1H), 7.14-7.37(m,28H)

EFFECT OF THE INVENTION

[0412] This invention concerns to novel β-lactam compounds which aremetabolically and hydrolytically stable against β-glycosidases, acidsand bases and having C-glycosides in the molecules and exert strongplasma cholesterol lowering effects and useful as plasma hypolipidemicagents.

1. The compounds have the following general formula (I);

wherein, A₁, A₃ and A₄ are hydrogen atom, halogen atom, alkyl grouphaving one to five carbon atoms, alkoxy group having one to five carbonatoms, —COOR₁, a following formula (b);

wherein, R₁ is hydrogen atom or alkyl group having one to five carbonatoms, or a following formula;

wherein, R₂ is —CH₂OH group, —CH₂OC(O)—R₁ group or —CO₂—R₁ group, R₃ is—OH group or —OC(O)—R₁ group, R₄ is —(CH₂)_(k)R₅(CH₂)_(l)— groupwherein, k and l are 0 or 1 more integer, k+l is 10 or fewer integer,further R₅ means bond and is single bond —, —CH═CH—, —OCH₂—, carbonylgroup or —CH(OH)—, and one of A₁, A₃ and A₄ in formula (I) is must bethe group in above mentioned formula (a), further A₂ is alkyl chainhaving one to five carbon atoms, alkoxy chain having one to five carbonatoms, alkenyl chain having one to five carbon atoms, hydroxyalkyl chainhaving one to five carbon atoms or carbonylalkyl chain having one tofive carbon atoms, n, p, q or r are 0, 1 or 2, or their pharmaceuticalacceptable salts.
 2. A method of preparing the compounds of generalformula (I) and their pharmaceutically acceptable salts comprisingStaudinger or Mannich reactions of the compounds of general formula(II);

wherein: A₁, A₂, R₃ and p are defined as aforesaid; X is leaving groupsuch as halogen atom or optically active sultam derivative, and thecompounds of general formula (III);

wherein, A₃, A₄, R₃, n, q and r are defined as aforesaid.
 3. A method ofpreparing the compounds of general formula (I) and theirpharmaceutically acceptable salts comprising reaction of the compoundsof general formula (IV);

wherein, n, q, r, A₃, A₄ and R₃ are defined as aforesaid, and thecompounds of general formula (V);